Whole-genome sequencing of chronic lymphocytic leukemia identifies subgroups with distinct biological and clinical features
Authors: Pauline Robbe, Kate E. Ridout, Dimitrios V. Vavoulis, Helene Dréau, Ben Kinnersley, Nicholas Denny, Daniel Chubb, Niamh Appleby, Anthony Cutts, Alex J. Cornish, Laura Lopez-Pascua, Ruth Clifford, Adam Burns, Basile Stamatopoulos, Maite Cabes, Reem Alsolami, Pavlos Antoniou, Melanie Oates, Doriane Cavalieri, J. C. Ambrose, P. Arumugam, R. Bevers, M. Bleda, F. Boardman-Pretty, C. R. Boustred, H. Brittain, M. A. Brown, Marc J. Caulfield, G. C. Chan, T. Fowler, A. Giess, A. Hamblin, S. Henderson, T. J. P. Hubbard, R. Jackson, L. J. Jones, D. Kasperaviciute, M. Kayikci, A. Kousathanas, L. Lahnstein, S. E. A. Leigh, I. U. S. Leong, F. J. Lopez, F. Maleady-Crowe, M. McEntagart, F. Minneci, L. Moutsianas, M. Mueller, N. Murugaesu, A. C. Need, P. O’Donovan, C. A. Odhams, C. Patch, D. Perez-Gil, M. B. Pereira, J. Pullinger, T. Rahim, A. Rendon, T. Rogers, K. Savage, K. Sawant, R. H. Scott, A. Siddiq, A. Sieghart, S. C. Smith, Alona Sosinsky, A. Stuckey, M. Tanguy, A. L. Taylor Tavares, E. R. A. Thomas, S. R. Thompson, A. Tucci, M. J. Welland, E. Williams, K. Witkowska, S. M. Wood, James Allan, Garry Bisshopp, Stuart Blakemore, Jacqueline Boultwood, David Bruce, Francesca Buffa, Andrea Buggins, Gerald Cohen, Kate Cwynarski, Claire Dearden, Richard Dillon, Sarah Ennis, Francesco Falciani, George Follows, Francesco Forconi, Jade Forster, Christopher Fox, John Gribben, Anna Hockaday, Dena Howard, Andrew Jackson, Nagesh Kalakonda, Umair Khan, Philip Law, Pascal Lefevre, Ke Lin, Sandra Maseno, Paul Moss, Graham Packham, Claire Palles, Helen Parker, Piers Patten, Andrea Pellagatti, Guy Pratt, Alan Ramsay, Andy Rawstron, Matthew Rose-Zerilli, Joseph Slupsky, Tatjana Stankovic, Andrew Steele, Jonathan Strefford, Shankar Varadarajan, Dimitrios V. Vavoulis, Simon Wagner, David Westhead, Sarah Wordsworth, Jack Zhuang, Jane Gibson, Anika V. Prabhu, Ron Schwessinger, Daisy Jennings, Terena James, Uma Maheswari, Martí Duran-Ferrer, Piero Carninci, Samantha J. L. Knight, Robert Månsson, Jim Hughes, James Davies, Mark Ross, David Bentley, Jonathan C. Strefford, Stephen Devereux, Andrew R. Pettitt, Peter Hillmen, Mark J. Caulfield, Richard S. Houlston, José I. Martín-Subero, Anna Schuh
Journal: Nature Genetics (2022)

Abstract The value of genome-wide over targeted driver analyses for predicting clinical outcomes of cancer patients is debated. Here, we report the whole-genome sequencing of 485 chronic lymphocytic leukemia patients enrolled in clinical trials as part of the United Kingdom’s 100,000 Genomes Project. We identify an extended catalog of recurrent coding and noncoding genetic mutations that represents a source for future studies and provide the most complete high-resolution map of structural variants, copy number changes and global genome features including telomere length, mutational signatures and genomic complexity. We demonstrate the relationship of these features with clinical outcome and show that integration of 186 distinct recurrent genomic alterations defines five genomic subgroups that associate with response to therapy, refining conventional outcome prediction. While requiring independent validation, our findings highlight the potential of whole-genome sequencing to inform future risk stratification in chronic lymphocytic leukemia.